The Wnt signaling pathway has critical roles in developmental pathways, including regulatory roles in cell proliferation, tissue patterning, and cell fate, migration, morphogenesis and function, as well as cell survival and degeneration (Logan and Nusse, Annu. Rev. Cell Dev. Biol. (2004) 20:781-810). Recently during research on stem cells, Wnt signaling pathway has been found to regulate the maintenance of epidermal stem cells, intestinal stem cells, hematopoietic stem cells, neural stem cells, embryonic stem cells and tumor stem cells (Reya and Clevers, Nature (2005) 434:843-850).
The canonical Wnt signaling pathway is activated by Wnt proteins that interact with seven-pass transmembrane receptors of the Frizzled (Fzd) family and single-pass transmembrane co-receptors, such as lipoprotein receptor-related protein 5/6 (LRP5/6). Such interaction activates the Wnt signaling pathway by recruiting and activating the Dishevelled (Dvl) protein, which, in turn, silences glycogen synthase kinase 3β (GSK3β) within a destructive complex formed by adenomatous polyposis coli (APC) protein, GSK3β, Axin, and a priming kinase for β-catenin called casein kinase 1α (CK1α). The destructive complex can phosphorylate β-catenin for its degradation. By inhibiting the destructive complex, cytoplasmic β-catenin can be stabilized and accumulated in the presence of lymphoid enhancing factor/T-cell factor (LEF/TCF) transcription factors so that β-catenin can be translocated into the nucleus to activate β-catenin mediated gene expressions of dease-causing products, including c-Myc, cyclin-D1, survivin, gastrin, VEGF, ASEF, etc., to increase cell proliferation (Boutros and Mlodzik, Mech. Dev. (1999) 83:27-37; and Perrimon, Cell (1994) 76:781-4).
Mutations or deregulated expression of components of the Wnt signaling pathway have been linked to the formation and metastasis of numerous tumors. For example, in patients with colon cancer, gene mutations have been observed in regulators of the Wnt cascade, including APC, β-catenin, Axin and TCF, leading to over-expression of genes associated with cell proliferation (Klaus and Birchmeier, Nat. Rev. Cancer (2008) 8:387-98). Aberrant activation of the Wnt signaling pathway is associated with a variety of diseases including various cancers (Hoang et al., Int. J. Cancer (2004) 109:106-111), decrease of neural precursor cells (Chenn and Walsh, Science (2002) 297:365-9), pathogenesis of sporadic medulloblastoma (Dahmen et al., Cancer Res. (2001) 61:7039-43), malignant proliferation of cancer cells due to disruption of Wnt signaling pathway in stem and progenitor cells (Reya and Clevers, Nature (2005) 434:843-850).
Thus, there is a need for agents and methods that modulate the Wnt signaling pathway, thereby treating, and/or ameliorating Wnt signaling-related disorders.